Of the known methods for the conjugation of molecules, the Huigsen [3+2] “click” chemistry and activated carboxylic acid conjugation reactions are perhaps two of most common. Scheme 1 shows the standard Huigsen [3+2] conjugation which uses Cu(I) as a catalyst. One of the drawbacks of this method is the need to use a metal catalyst.

Scheme 2 shows the classic activated carboxylic acid-amine conjugation using N-hydroxysuccinamide as the activating group.

The N-hydroxysuccinamide activated ester is one of the best-selling bio-conjugation reagents. One of the drawbacks of this reagent is the necessity to remove the N-hydroxysuccinamide side product formed in the reaction.
Nagasaki et al.1 describe the reaction between a bioactive compound having at least one amino group with a functionalized polyethylene glycol having a structure that allows reaction of two aldehyde groups with one amino group to form two covalent bonds.
Miao et al.2 describe a conjugation reaction between an amine and a dialdehyde in the presence of a reducing agent (NaBH3(CN)) at a pH of 3-9 to provide a fully saturated cyclic structure.